title: Lipid analogues as potential drugs for the regulation of mitochondrial cell death.
abstract: The mitochondrion plays an important role in the production of energy as ATP, the regulation of cell viability and apoptosis, and the biosynthesis of major structural and regulatory molecules, such as lipids. During ATP production, reactive oxygen species are generated that alter the intracellular redox state and activate apoptosis. Mitochondrial dysfunction is a well-recognized component of the pathogenesis of diseases such as cancer. Understanding mitochondrial function, and how this is dysregulated in disease, offers the opportunity for the development of drug molecules to specifically target such defects. Altered energy metabolism in cancer, in which ATP production occurs largely by glycolysis, rather than by oxidative phosphorylation, is attributable in part to the up-regulation of cell survival signalling cascades. These pathways also regulate the balance between pro- and anti-apoptotic factors that may determine the rate of cell death and proliferation. A number of anti-cancer drugs have been developed that target these factors and one of the most promising groups of agents in this regard are the lipid-based molecules that act directly or indirectly at the mitochondrion. These molecules have emerged in part from an understanding of the mitochondrial actions of naturally occurring fatty acids. Some of these agents have already entered clinical trials because they specifically target known mitochondrial defects in the cancer cell.
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney, Sydney, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
authors.forename: Herryawan Ryadi Eziwar
authors.initials: HR
authors.lastname: Dyari
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Allison
authors.forename: Tristan
authors.initials: T
authors.lastname: Rawling
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010743:Phospholipids / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D005227:Fatty Acids; D010743:Phospholipids; D000255:Adenosine Triphosphate
keywords: N-acylethanolamines; cancer cell; ether phospholipids; fatty acid biotransformation; free fatty acids; intrinsic pathway of apoptosis; mitochondrial ATP production; polyunsaturated fatty acid epoxides; reactive oxygen species